Review Article

Current Status of Screening in Cancer Cervix

Ashok Kumar Padhy, B L Nayak, J. Mohapatra, J Parija, S K Giri
Department of Gynec. Oncology
AH Regional Cancer Centre,Cuttack

Cervical Cancer is the leading cause of morbidity, mortality among women in developing countries. As per GLOBOCON 2002(IARC) data, 500,000 women are diagnosed & 270,000 deaths occur per year. Projections indicate by 2050, more than 1 million new cases of cervical cancer will be there each year. Although Prevention, early detection and treatment are established to be highly effective in controlling cervical cancer, unfortunately these are not optimaly utilized in developing countries. So, the reality about this cancer is though preventable but not yet prevented. The objective of Cervical cancer screening is to prevent the occurrence of Invasive Cervical Cancer by detecting in pre-invasive stages. Screening tests like traditional Pap tests, Liquid based Cytology, Visual Inspection with Acetic Acid (VIA) and Lugols Iodine (VILI) and HPV testing though have their own pros & cons but if conducted in a proper way have optimal accuracy in detecting CIN , early asymptomatic preclinical invasive cancer. Effective therapy like Cryotherapy , Laser Ablation and Conisation, Loop Electrosurgical Excision Procedure (LEEP),Cold knife Coagulation are widely available to tackle these Precancerous conditions . Pap test still remains to be most practical, effective, fairly sensitive and quite efficient to pin point the suspicious group in which further evaluation is required. Its role in mass screening is unquestionable. Colposcopy is a most useful aid to triage women with positive tests, to assess the nature and extent of precancerous lesions & guide to take biopsy from exact side whenever needed.The overall accuracy for detection improves maximum if cytology and colposcopy are simultaneously combined.It is well told " Cytology discovers the crime and Colposcopy locates the culprit".

"The first observation of Cancer cells in a smear was the most thrilling experience of my scientific career".

Dr George Nicholas Papanicolaou,1928

From the era of Papanicolaou who was nominated for Nobel Prize to H Z Hausen, who received nobel prize in the yr 2008 for his work on HPV, there has been a lot of innovations, changes and modifications in the field of screening of Cancer Cervix. It was Dr Papanicolaou who first spread the concept of Cervical smear in 1928, considered as father of Modern Cytology. In 1941, his research work published in American J of Obstet. & Gynecol titled "Diagnosis of Uterine Cancer by Vaginal Smear" created a lot of enthusiasm among various workers worldwide in the field of screening.

Traditional Pap test has been successful in reducing the incidence of Cervical Cancer by 79% and mortality by 70% since 1950 but with a false negative rate of 49% in detecting cancer precursor lesions. Screening error can occur in 3 stages: Smear taking affecting smear quality, Preparation of slides and interpretation by cytologists. To alleviate sampling and preparation errors newer techniques have been developed to provide more representative cell samples of evenly dispersed cells in a thin layer (monolayer) which aims to reduce material such as blood ,pus and mucus from obscuring cells during cytological examination. The newer techniques are based on high speed video microscopy image interpretation software & field of view computers to analyze and classify images of Pap smear .Among these Liquid based screening (LBS) including Thin Prep (Cytyc Corporation) & Auto Cyte Prep (tripath imaging which is a computerized image processing device) have gained much popularity in the developed world. Liquid based Cytology transmits 80-90% cells to the media, eliminates air drying. It reduces the rate of unsatisfactory smears of traditional pap test by 70% to 90%.LBS has been used by 90% gynaecologists in United States since 2003.

Over the last decade, remarkable progress has been made in understanding Cervical Carcinogenesis. An overwhelming body of evidences show that infection with various high risk Human Papilloma Virus (HPV) is the central and necessary cause for development of Cervical Cancers & its precursor lesions. This fact was exploited for development of molecular technologies for viral detection to overcome the limitations of Cytology as screening procedure. HPV DNA testing identifies women at risk for developing cervical neoplasia without the inherent subjectivity to cytology.HPV test can detect HPV DNA in exfoliated cervical cells which can detect about 100% Invasive Cancers, 75-90% precancerous lesions (LSIL,CIN,HSIL) and 50% equivocal smear (ASCUS).Various HPV testings are being utilized as primary screening, triage of equivocal pap smears or ASCUS and follow up after treatment of CIN.

HPV Testing has a higher Sensitivity and negative predictive value for detection of pre-invasive disease than cytology. But its important drawback is lower specificity and low positive predictive value for high grade lesions. Outcome of HPV test as a primary screening procedure (Various RCTs from Europe) states that there is definite reduction in incidence of high grade CIN ,3 to 5 yrs after screening .LSIL and ASCUS represent the largest fraction of abnormalities in cervical cancer screening. The ASCUS-LSIL Triage study has investigated in a prospective ,randomized fashion for optimal management of LSIL and ASCUS by immediate Colposcopy ,HPV Triage and repeat cytology concluded that HPV Triage seemed to be at least as sensitive as immediate colposcopy in detection of high grade CIN ,where need for Colposcopy referrals was halved. So HPV triage is the best strategy for management of women with ASCUS and this fact was incorporated recently in international guidelines.HPV Testing was also suggested to predict residual or recurrent CIN in women treated for high grade cervical lesions.

The two methods widely used for HPV detection are PCR and Hybrid Capture II (HC,Qiagen,Digene Corp).HC2 is a nuceic acid hybridization assay for qualitative detection of DNA of 13 oncogenic(Probe A) and 5benign(Probe B) HPV types in clinical specimen. It is the only HPV test approved by Food & Drug Administration (FDA ) for ASCUS triage and cervical cancer screening in combination with Cytology after the age of 30 yrs. Among PCR techniques consensus PCR and type specific PCR are commonly used. Roche Amplicor HPV test is a commercial PCR based assay for HPV detection which involves a pool of 13 HR -HPV as included in HC2 assay. The most advanced HPV Genotyping approaches are more appropriate for the identification of individuals at risk of disease than its presence or absence. After consensus PCR amplifications, HPV types can be discriminated by Reverse Hybridization with type specific probes. SPF PCR is a commercial INNO –LiPA HPV assay which is capable of genotyping 25 different HPV types. Among the most recent tests, HPV Viral Load, HPV integration E2 status ,HPV RNA detection (Pre Tect HPV Proofer) are promising for screening of Cancer Cervix for the future. Outcome from translational research also identifies markers that reflect dysregulation of cell cycle in cervical neoplasia such as p 16, Ki -67 ,MCM Proteins and Cyclin E which are expected to be included in screening of Cancer cervix in future.